Posurdex Inhibits Retinal Vasculopathy and Neuropathy by Intravitreal Vascular Endothelial Growth Factor (VEGF) in Monkeys

Abstract

Abstract: : Purpose:Posurdex® is a proprietary drug delivery system that delivers dexamethasone to the back of the eye for sustained release. This study evaluated the efficacy of 700 µg Posurdex® at inhibiting retinal changes induced by VEGF in monkeys. VEGF is associated with the pathologies of a variety of retinal disorders, including diabetic and occlusive vasculature retinopathies, and choroidal neovascularization. Methods: Six cynomolgus monkeys weighing 3 – 4.5 kg were used in this study. OS eyes of 3 animals received Posurdex® through the pars plana region (infero–temporal) via a 22–gauge applicator system; the OS eyes of the other 3 animals were injected with the applicator, and served as the control group. One–week later, a single injection of 1.25 µg VEGF_h165, in a 50 µl volume was injected via a 30–gauge needle 1–2 mm over the macula in the OS eyes of all 6 monkeys. Follow–up measurements were made at pre–Posurdex® (baseline), pre–VEGF, ½ week, 1, 2 and 4 weeks post–VEGF, for the following endpoints: IOP, anterior chamber slit lamp inspection, optic nerve head topography with the HRT, retinal vessel vasculopathy by fundus photography and fluorescein angiography (tortuosity, vessel caliber, leak), foveal and para–foveal retinal thicknesses with the OCT, and retinal neurosensory function with simultaneous bilateral flash ERG using the Espion® ColorDome® electrophysiology system. Results:VEGF produced peaked vascular and neuronal effects at T = ½ and 1 week, which were resolved at subsequent follow–up times (2 weeks and 4 weeks). Posurdex® did not change any endpoints in the naïve eye, but significantly inhibited the effects produced by VEGF. In the anterior segment, Posurdex® reduced flare from 4 ± 0 (0–4 scale) to 2 ± 1; p=0.02. This profile was similar in the posterior pole: Posurdex® reduced the VEGF–induced increase in retinal vein tortuosity from 10 ± 2% to 3 ± 1%. Other VEGF–induced effects were also reduced: retinal vein caliber increase (21 ± 3% to 5 ± 5%; p=0.04), retinal vessel leak (2 ± 1 to 0 ± 0, 0–3 scale; p=0.02), para–foveal retinal thickness increase (15 ± 4% to 4 ± 1%; p=0.03), optic nerve head cup volume decrease (–95 ± 3% to 15 ± 15%; p=0.005), and ERG b–wave amplitude reduction (–54 ± 13% to 11 ± 16% @ 1 cd.s/m²; p=0.03). Conclusions: The 700 µg formulation of Posurdex® reduced VEGF–induced anterior segment inflammation, retinal vasculopathy and neuropathy and was safe in monkeys.

Keywords: retina • corticosteroids • pharmacology